The overall goal of this proposal is to better understand how natural killer (NK) cells control viral infections. It is clear that NK cells play a vital role in early, innate immunity against pathogens, especially herpesviruses, such as cytomegalovirus (CMV). CMV is an important human pathogen, particularly in immunocompromised patients such as those with HIV/AIDS and transplant recipients. Moreover, humans with a selective deficiency in NK cells suffer from recurrent viral infections, including CMV. However, human CMV cannot be studied in small animal models for more detailed analysis of how NK cells control this virus. But studies of murine CMV (MCMV), a natural pathogen of mice, recapitulates many features of HCMV infection. Prior studies clearly indicate that a central component of how NK cell control MCMV in C57BL/6 mice is the NK cell activation receptor, Ly49H, which recognizes m157, encoded by MCMV. The interaction between Ly49H and m157 is required for effective control and survival from infection. However, in the absence of inflammation, Ly49H+ NK cells are not activated, suggesting that NK cells must receive other signals, perhaps from cytokines, in order to become efficient effector cells. Moreover, the initially infected cell is a reticular fibroblast in the spleen which produces cytokines and chemokines that appear to initiate the immune response and may affect NK cell functions. How these cells are activated by MCMV is not known but available evidence from the study of other viruses suggest that they may use a cytosolic sensor to detect the virus and stimulate cytokine production. But the role of cytosolic sensors for large DNA viruses like MCMV has not been established. Therefore, the specific aims of this proposal are to: 1) Determine mechanism by which initially infected cells respond to MCMV infection. 2) Determine intravital behavior of virus-specific NK cells with MCMV-infected cells. 3) Examine cytokine second signals for NK cells to be effectively activated by targets. These studies will provide significant insight into the molecular basis for host anti-viral defense in innate immunity provided by NK cells.